Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain

ABSTRACT

Compounds of formula (I),  
                 
 
     or a pharmaceutically acceptable salt or solvate thereof, wherein P, P′, W, R 1 , R 2 , n, p, q, r, s and t are as defined in the specification, processes for preparing such compounds, pharmaceutical compositions comprising such compounds and their use in therapy.

This invention relates to novel compounds, especially urea derivatives,having pharmacological activity, processes for their preparation, tocompositions containing them and to their use in medicine, especially inthe treatment of various disorders.

Vanilloids are a class of natural and synthetic compounds that arecharacterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl)group or a functionally equivalent group. Vanilloid Receptor (VR1),whose function is modulated by such compounds, has been widely studiedand is extensively reviewed by Szallasi and Blumberg (The AmericanSociety for Pharmacology and Experimental Therapeutics, 1999, Vol. 51,No. 2.).

A wide variety of Vanilloid compounds of different structures are knownin the art, for example those disclosed in European Patent ApplicationNumbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB2226313 and International Patent Application, Publication Number WO92/09285. Particularly notable examples of vanilloid compounds orvanilloid receptor modulators are capsaicin or trans8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plantcapsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or—N-(4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).

U.S. Pat. No. 3,424,760 and U.S. Pat. No. 3,424,761 both describe aseries of 3-ureidopyrrolidines that are said to exhibit analgesic,central nervous system, and psychopharmacologic activities. Thesepatents specifically disclose the compounds1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.

International Patent Application, Publication Number WO 97/43255,discloses azetidinylurea derivatives as inhibitors of microsomaltriglyceride transfer protein.

International Patent Applications, Publication Numbers WO 02/08221, WO02/16317, WO 02/16318 and WO 02/16319 each disclose certain vanilloidreceptor antagonists and their use in the treatment of diseasesassociated with VR1 activity.

International Patent Applications, Publication Numbers WO 02/072536 andWO 02/090326, and International Patent Application, Publication NumberWO 03/022809 (published after the priority date of the presentapplication) disclose a series of urea derivatives and their use in thetreatment of diseases associated with VR1 activity. None of theseapplications discloses azetidinylurea derivatives in particularazetidin-3-ylurea derivatives.

According to a first aspect of the present invention, there is provideda compound of formula (I),

or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:P and P′ are independently selected from aryl and heteroaryl;R¹ and R² are independently selected from —H, halo, alkyl, alkoxy,cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN,—NO₂, —OH, —OCF₃, —CF₃, —NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶,—OS(O)₂CF₃, —O(CH₂)_(X)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,—C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(X)OR⁶, —C(O)(CH₂)_(X)NR⁴R⁵,—C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(X)C(O)alkoxy, —(CH₂)_(X)OC(O)R⁶,—(CH₂)_(X)OR⁶, —(CH₂)_(X)NR⁴R⁵, —(CH₂)_(X)C(O)NR⁴R⁵,—(CH₂)_(X)N(R⁴)C(O)R⁶, —(CH₂)_(X)S(O)₂NR⁴R⁵, —(CH₂)_(X)N(R⁴)S(O)₂R⁶,-ZAr, —(CH₂)_(X)S(O)₂R⁶, —(OCH₂)_(X)S(O)₂R⁶, —N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶or —(CH₂)_(X)C(O)alkyl;R⁴ and R⁵ may be the same or different and represent H or alkyl or R⁴and R⁵ together with the atoms to which they are attached form aC₃₋₆azacycloalkane, C₃₋₆(2-oxo)azacycloalkane ring or C₅₋₈ polymethylenechain optionally interrupted by heteroatoms;Z represents O, S or NR⁷;W represents a bond or a group CH or (CH₂)CH;R⁶ represents alkyl or aryl;R⁷ represents hydrogen, alkyl or aryl;m represents and integer 1 or 2;n represents and integer 0, 1, 2 or 3;p and q independently represent an integer 0, 1, 2, 3 or 4;when W is a bond, t represents 1, r represents an integer 0 or 1, and srepresents an integer 0 or 1, such that r+s=1;when W is a group CH or (CH₂)CH, t represents 2, r represents an integer0, 1, 2 or 3, and s represents an integer 0, 1 or 2; andx represents an integer 0, 1, 2, 3, 4, 5 or 6.

Examples of the C₃₋₆azacycloalkane ring that R⁴ and R⁵ may independentlyrepresent, when taken together with the atoms to which they areattached, include pyrrolidine and piperidine.

Examples of the C₃₋₆(2-oxo)azacycloalkane ring that R⁴ and R⁵ mayindependently represent, when taken together with the atoms to whichthey are attached, include pyrrolidinone and piperidinone.

Examples of the C₅₋₈ polymethylene chain optionally interrupted byheteroatoms that R⁴ and R⁵ may independently represent when takentogether with the atoms to which they are attached, include a C₅₋₈polymethylene chain optionally interrupted by heteroatoms such as 0 or—NR⁷. Specific examples include morpholine and piperazine.

When p or q represent 2, 3 or 4 the groups R¹ or R² may be the same ordifferent.

Preferably, P represents phenyl, naphthyl, quinolinyl, cinnolinyl orisoquinolinyl, more preferably phenyl, cinnolinyl or isoquinolinyl,particularly phenyl, 5-cinnolinyl or 5-isoquinolinyl. More preferably,when W is a bond, P represents phenyl or 5-isoquinolinyl, especiallyphenyl, and, when W is CH or (CH₂)CH, P represents 5-cinnolinyl or5-isoquinolinyl, especially 5-isoquinolinyl. When W is CH or (CH₂)CH,another P group of interest is phenyl.

Preferably, P′ represents a 6-membered aromatic ring e.g. phenyl,pyrimidinyl or pyridyl, especially phenyl or pyridyl e.g. 2-pyridyl.More preferably, when W is a bond, P′ represents phenyl or pyridyl,especially 2-pyridyl, and, when W is CH or (CH₂)CH, P′ representsphenyl.

Preferably, R¹ represents halo, —CF₃ or alkyl. More preferably, R¹represents fluoro, chloro, bromo, —CF₃, methyl or tert-butyl, especiallyfluoro, chloro, bromo, —CF₃ or methyl, more especially fluoro, chloro,bromo or methyl In particular, when W is a group CH or (CH₂)CH, R¹preferably represents methyl. When W is a group CH or (CH₂)CH, anotherR¹ substituent of interest is bromo. When W is a bond, R¹ preferablyrepresents chloro or bromo.

Preferably, p represents 1 or 2. More preferably, p represents 1.

Particular groups which (R¹)_(p)P— may represent include, 2-, 3- or4-halophenyl or 2,3- or 2,5-dihalophenyl e.g. 2-bromophenyl,2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 2,3-dichlorophenyl or2,5-dichlorophenyl, 2- or 3-trifluoromethylphenyl,2-methyl-3-chlorophenyl, 1- or 3-methylisoquinolin-5-yl,1,3-dimethylisoquinolin-5-yl or 3-methylcinnolin-5-yl.

Preferably, m represents 1.

Preferably, n represents 0 or 1. More preferably, n represents 0.

Preferably, R² represents halo, alkyl, alkoxy, —CN or —CF₃. Morepreferably R² represents fluoro, chloro, bromo, methyl, OMe or CF₃. Inparticular, when W is a bond R² preferably represents methyl or —CF₃,especially —CF₃, and, when W is CH or (CH₂)CH, R² preferably representshydrogen or fluoro especially hydrogen.

Preferably, q represents 0, 1 or 2. More preferably, q represents 1 or2, especially q represents 1. However in one set of compounds ofparticular interest (notably when W is CH or (CH₂)CH and P′ representsphenyl) q represents 0.

Preferably, x represents 1, 2 or 3.

When q represents 1 or 2, and P′ represents a 6-membered aromatic ringsuch as phenyl or pyridyl (e.g. 2-pyridyl), particularly preferredexamples of R² are when W is a bond, 3-trifluoromethyl,4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl,6-methyl-4-trifluoromethyl and 6-methyl-5-trifluoromethyl; and when W isCH or (CH₂)CH, hydrogen and halo (preferably 4-fluoro).

When W is CH or (CH₂)CH, preferably, r+s represents 1, 2, 3 or 4, morepreferably 1 or 2, especially 1.

It is especially preferred that r=0 and s=1.

A first group of compounds of particular interest is that in which Wrepresents a bond. A second group of compounds of particular interest isthat in which W represents CH or (CH₂)CH, particularly CH.

Preferably W represents a bond or CH, most preferably a bond.

Preferably R⁴ represents methyl or hydrogen

Preferably R⁵ represents methyl or hydrogen.

Preferably R⁶ represents methyl.

Preferably R⁷ represents methyl or hydrogen.

Preferably Z represents a bond.

A particularly preferred group of compounds is that in which r=0, s=1and P′ represents phenyl or 2-pyridyl. In particular, compounds ofinterest are those in which r=0, s=1, W represents CH or (CH₂)CH(especially CH) and P′ represents phenyl. Also those in which r=0, s=1,W represents a bond and P′ represents 2-pyridyl.

When t is 1, r=1, s=0 and P′ is phenyl, P is preferably not phenyl ornaphthyl.

While the preferred groups for each variable have generally been listedabove separately for each variable, preferred compounds of thisinvention include those in which several or each variable in formula (I)is selected from the preferred, more preferred, or most preferred groupsfor each variable. Therefore, this invention is intended to include allcombinations of preferred, more preferred, and most preferred groups.

Compounds of formula (I) of particular interest according to the presentinvention are Example numbers 1 to 41 (presented below) orpharmaceutically acceptable salts or solvates thereof.

Certain of the carbon atoms of formula (I) are chiral carbon atoms, suchas the carbon atom marked with an “*”, and therefore compounds offormula (I) may exist as stereoisomers. The invention extends to alloptical isomers such as stereoisomeric forms of the compounds of formula(I) including enantiomers and mixtures thereof, such as racemates. Thedifferent stereoisomeric forms may be separated or resolved one from theother by conventional methods or any given isomer may be obtained byconventional stereospecific or asymmetric syntheses.

An example set of compounds of formula (I) have the C* carbon in theR-configuration.

Certain of the compounds herein can exist in various tautomeric formsand it is to be understood that the invention encompasses all suchtautomeric forms.

As indicated above, the compounds of formula (I) can form salts,especially pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts are those use conventionally in the art and includethose described in J. Pharm. Sci., 1977, 66, 1-19, such as acid additionsalts.

Suitable pharmaceutically acceptable salts include acid addition salts.

Suitable pharmaceutically acceptable acid addition salts include saltswith inorganic acids such, for example, as hydrochloric acid,hydrobromic acid, orthophosphoric acid or sulphuric acid, or withorganic acids such, for example as methanesulphonic acid,toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citricacid, fumaric acid, malic acid, succinic acid, salicylic acid, maleicacid, glycerophosphoric acid or acetylsalicylic acid.

The salts and/or solvates of the compounds of the formula (I) which arenot pharmaceutically acceptable may be useful as intermediates in thepreparation of pharmaceutically acceptable salts and/or solvates ofcompounds of formula (I) or the compounds of the formula (I) themselves,and as such form another aspect of the present invention.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and if crystalline, may be optionally hydrated orsolvated. This invention includes in its scope stoichiometric hydratesas well as compounds containing variable amounts of water.

Suitable solvates include pharmaceutically acceptable solvates, such ashydrates.

Solvates include stoichiometric solvates and non-stoichiometricsolvates.

As used herein the term “alkyl” as a group or part of a group refers toa straight or branched chain saturated aliphatic hydrocarbon radicalcontaining 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Suchalkyl groups in particular include methyl (“Me”), ethyl (“Et”), n-propyl(“Pr^(n)”), iso-propyl (“Pr^(i)”), n-butyl (“Bu^(n)”), sec-butyl(“Bu^(s)”), tert-butyl (“Bu^(t)”), pentyl and hexyl. The term“cycloalkyl” as part of a group refers to a saturated alicyclichydrocarbon radical containing 3 to 12 carbon atoms, suitably 3 to 6carbon atoms. Where appropriate, such alkyl groups may be substituted byone or more groups selected from halo (such as fluoro, chloro, bromo),—CN, —CF₃, —OH, —OCF₃, C₂-6 alkenyl, C₃₋₆ alkynyl, C₁₋₆ alkoxy, aryl anddi-C₁₋₆ alkylamino. Preferably alkyl is unsubstituted.

As used herein, the term “alkoxy” as a group or part of a group refersto an alkyl ether radical, wherein the term “alkyl” is defined above.Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Whereappropriate, such alkoxy groups may be substituted by one or more groupsselected from halo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH,—OCF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkynyl, aryl and di-C₁₋₆alkylamino. Preferably alkoxy is unsubstituted.

As used herein, the term “aryl” as a group or part of a group refers toa carbocyclic aromatic radical (“Ar”). Suitably such aryl groups are 6membered monocyclic groups or 8-10 membered fused bicyclic groups(including aromatic ring systems fused with non-aromatic ring systems),especially phenyl (“Ph”), biphenyl, indene and naphthyl, particularlyphenyl.

Aryl groups contained within moieties R¹, R², R⁶ or R⁷ may optionally besubstituted (and in the case of bicyclic groups containing an aromaticsystem fused with a non-aromatic systems may optionally be substitutedon either or both of the aromatic and the non-aromatic portion) with oneor more substituents selected from the list consisting of halo, hydroxy,carbonyl, alkoxy, alkyl, —CF₃, NR⁴R⁵ and —SO₂R⁶.

As used herein, the term “heteroaryl” as a group or part of a grouprefers to a stable 5- 7-membered monocyclic or 7- to 10-memberedbicyclic heterocyclic aromatic ring (including an aromatic ring systemfused with a non-aromatic ring system) which consists of carbon atomsand from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S. It is preferred that the total number of S andO atoms in the aromatic heterocycle is not more than 1. Examples ofsuitable heteroaryl groups include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrobenzofuranyl,furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolinyl, indolyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, phthalazinyl, pteridinyl,purinyl, pyrazinyl, pyrazolyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl andxanthenyl.

The term “halo” is used herein to describe, unless otherwise stated, agroup selected from fluorine (“fluoro”), chlorine (“chloro”), bromine(“bromo”) or iodine (“iodo”).

The term “naphthyl” is used herein to denote, unless otherwise stated,both naphth-1-yl and naphth-2-yl groups.

The term “pyridyl” includes 2-pyridyl, 3-pyridyl and 4-pyridyl butpreferably denotes 2-pyridyl. The term pyrimidinyl includes2-pyrimidinyl.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises coupling a compound of formula (II):

in which R¹, P and p are as defined in formula (I) with a compound offormula (III):

in which P′, R², W, n, q, r, s and t are as defined in formula (I) and Aand B contain appropriate functional groups which are capable ofreacting together to form the urea moiety;and thereafter, as necessary, carrying out one or more of the followingreactions:(i) converting one compound of formula (I) into another compound offormula (I);(ii) removing any protecting group;(iii) preparing a salt or a solvate of the compound so formed.

Suitable examples of appropriate A and B groups include:

(a) A is —N═C═O and B is NH₂; or A is NH₂ and B is N═C═O or

(b) A is NH₂ and B is NH₂ together with an appropriate urea formingagent.

In process (a) the reaction is typically carried out in an inert solventsuch as dichloromethane or acetonitrile.

In process (b) the urea forming agent can be carbonyl diimidazole orphosgene or triphosgene, and carried out in an inert organic solventsuch as diethyl ether, tetrahydrofuran or DCM at ambient or elevatedtemperature in the presence of a base such as triethylamine or pyridine.

An alternative method of synthesis of the unsymmetrical urea compoundsof formula (I) is from a diaryl carbonate, via the correspondingcarbamate. Such a methodology is described by Freer et al. (SyntheticCommunications, 26(2), 331-349, 1996). It would be appreciated by thoseskilled in the art that such a methodology could be readily adapted forpreparation of the compounds of formula (I).

A compound of formula (III) may be prepared by reaction of a compound offormula (IV):

wherein, P′, W, t, q and R² as defined above and L¹ is a leaving group,with a compound of formula (V):

wherein B, n, r and s are as defined above, or a protected derivativethereof. When B represents an amine group, preferably it is employed asa protected derivative; examples of amine protecting groups arementioned below.

Suitably L¹ is a halogen, such as chlorine.

Suitably, the compound of formula (V) is in an activated form, forexample an ionic form. Such activated forms are prepared usingconventional coupling reaction methodology, as for example by reactingcompounds (IV) and (V) in the presence of an alkali carbonate, such aspotassium carbonate, in an aprotic solvent such as dimethylformamideusing reaction conditions appropriate to the particular methodologychosen, for example at an elevated temperature, such as 100° C.

Compounds of formulae (IV) and (V) are commercially available, or areprepared by known procedures, such as those disclosed in: Heterocycles,1984, 22(1), 117, J. Chem. Soc., Perkin 1, 1988, 4, 921 and J. Org.Chem., 1991, 56, 6729 for compounds of formula (IV) and J. Med. Chem.,1992, 35(10), 1764 for compounds of formula (V), or by methods analogousto these disclosed methods.

Compounds of formula (II) are either known or may be prepared by knownmethods, or methods analogous to those described herein.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove-mentioned procedures. Standard protection and deprotectiontechniques, such as those described in Greene T. W. ‘Protective groupsin organic synthesis’, New York, Wiley (1981), can be used. For example,primary amines can be protected as phthalimide, benzyl,benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can beprotected as esters. Aldehyde or ketone groups can be protected asacetals, ketals, thioacetals or thioketals. Deprotection of such groupsis achieved using conventional procedures well known in the art.

In particular in the reaction of compounds of formula (IV) and (V) thegroup B preferably represents —NH(t-BOC)—.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Any novel intermediates used in the synthesis of the compounds offormula (I) are also included within the scope of the invention.Therefore according to the invention there is provided a compound offormula (IIIA):

in which P′, R², W, n, q, r, s and t are as defined in formula (I) and Bis NH₂ or N═C═O.

The preferences for the groups P′, R², W, n, q, r, s and t in formula(IIIA) are the same as those described for formula (I) above.

Specific compounds of formula (IIIA) include:

-   1-(5-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   1-(3-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   1-(4-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   1-(6-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   1-(6-Methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   1-(6-Methyl-5-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;-   3-Amino-1-diphenylmethylazetidine; and-   3-Amino-1-di-(4-fluorophenyl)methylazetidine.

Compounds of formula (I) and their pharmaceutically acceptable saltshave Vanilloid receptor antagonist (VR1) activity and are believed to beof potential use for the treatment or prophylaxis of certain disorders,or treatment of the pain associated with them, such as: pain, chronicpain, neuropathic pain, postoperative pain, postrheumatoid arthriticpain, osteoarthritic pain, back pain, visceral pain, cancer pain,algesia, neuralgia, dental pain, headache, migraine, neuropathies,carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy,post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury,ischaemia, neurodegeneration, stroke, post stroke pain, multiplesclerosis, respiratory diseases, asthma, cough, COPD, bronchoconstriction, inflammatory disorders, oesophagitis, heart burn,Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder(GERD), stomach and duodenal ulcers, functional dyspepsia, irritablebowel syndrome, inflammatory bowel disease, colitis, Crohn's disease,pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic,urinary incontinence, cystitis, burns, itch, psoriasis, pruritis, emesis(hereinafter referred to as the “Disorders of the Invention”).

Accordingly, the invention also provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, for use as anactive therapeutic substance, in particular in the treatment and/orprophylaxis of the Disorders of the Invention.

In particular, the invention provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in thetreatment or prophylaxis of pain.

The invention further provides a method for the treatment or prophylaxisof disorders in which antagonism of the Vanilloid (VR1) receptor isbeneficial, in particular the Disorders of the Invention, in mammalsincluding humans, which comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof.

The invention provides for the use of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof in the manufactureof a medicament for the treatment or prophylaxis of disorders in whichan antagonist of the Vanilloid (VR1) receptor is beneficial,particularly the Disorders of the Invention.

In order to use the compounds of the invention in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. Thus, the present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof anda pharmaceutically acceptable carrier or excipient therefor.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral, rectal administration orintravesical adminstration to the bladder and, as such, may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable or infusable solutions,suspensions or suppositories. Orally administrable compositions aregenerally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors. Forsystemic administration, dosage levels from 0.01 mg to 100 mg perkilogramme of body weight are useful in the treatment of pain. However,as a general guide suitable unit doses may be 0.05 to 1000 mg, moresuitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5and 0.1 to 250 mg; and such unit doses may be administered more thanonce a day, for example two or three a day, so that the total dailydosage is in the range of about 0.5 to 1000 mg; and such therapy mayextend for a number of weeks or months.

No unacceptable toxicological effects are indicated with compounds ofthe invention when administered in accordance with the invention.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofthe compounds of the invention.

Abbreviations

BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

HPLC—High Perfomance Liquid Chromatography

MgSO₄— Magnesium sulfate

TFA—Trifluoroacetic acid

DCM—dichloromethane

Description 1

1,3-Dimethyl-5-nitroisoquinoline (D1)

1,3-Dimethylisoquinoline [(Chem. Left., 1983, p. 791), 2.39 g, 15.20mM], in concentrated sulfuric acid, (15 ml), was cooled to <4° C. Asolution of potassium nitrate, (1.69 g, 16.72 mM), in concentratedsulfuric acid was added dropwise, maintaining the temperature below 4°C. After complete addition the solution was stirred at this temperaturefor a further 2 h then warmed to room temperature for 1 h. The reactionmixture was poured into ice water and the solution basified with sodiumhydroxide and extracted with DCM. The extract was washed with brine,dried and concentrated to a yellow solid. Purification by silica gelchromatography afforded the title compound as a yellow crystallinesolid.

Description 2

5-Amino-1,3-dimethylisoquinoline (D2)

A solution of D1 (2.01 g, 9.94 mM) and 10% palladium on charcoal (1 g)in methanol was hydrogenated at atmospheric pressure for 1 h. Thecatalyst was filtered off and the filtrate concentrated under reducedpressure to afford the title compound as an off white solid.

Description 3

3-Methyl-5-nitroisoquinoline (D3)

A solution of 3-methylisoquinoline (5.4 g, 0.038 mol) in concentratedsulfuric acid (30 ml) was cautiously added to a solution of potassiumnitrate (4.25 g, 1.1 eq) in concentrated sulfuric acid (23 ml) whilstmaintaining the temperature below 4° C. (ice bath). Stirring wascontinued for 2 h and then temperature raised to ambient. Reaction wasfurther stirred for 3 h and then poured into ice-water slurry (500 ml).Neutralisation using solid potassium carbonate affored a yellow solidwhich was filtered and washed with water. The crude product wasdissolved in ethanol (200 ml), filtered and concentrated under reducedpressure to afford the title compound as a yellow solid.

Description 4

5-Amino-3-methylisoquinoline (D4)

The title compound was prepared from D3 using the procedure outlined inD2.

Description 5

5-Amino-1-methylisoquinoline (D5)

The title compound was prepared in a similar manner to that of K. C.Agrawal, B. A. Booth, A. C. Sartorelli, J. Med. Chem., 1968 11 700.

5-Amino-3-methylcinnoline is available commercially. Di-tert-butyltricarbonate was prepared according to the procedure outlined in theliterature (Org. Synth., 1978, 57, p. 45).

Description 6

[1-(5-Trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acid t-butylester. (D6)

3-Butoxycarbonylaminoazetidine, acetic acid salt (synthesis described inWO 98/57640) (1 g, 4.31 mM) in dry DMF (10 ml) was treated with2-chloro-5-trifluoromethylpyridine (938 mg, 5.17 mM) and potassiumcarbonate (1.43 g, 10.33 mM). The mixture was heated to 100° C.overnight. The solution was diluted with ethyl acetate, washed withwater (3×), brine, dried (MgSO₄) and concentrated. Purification bysilica gel chromatography gave the title compound as a colourless solid,(750 mg).

Description 7

1-(5-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine. (D7)

D6 (750 mg, 1.28 mM) in dichloromethane (5 ml) was treated withtrifluoroacetic acid (5 ml) overnight at ambient temperature. Thesolution was concentrated and then partitioned between dichloromethaneand 2M sodium hydroxide. The dichloromethane solution was washed withbrine, dried and concentrated to give the title compound as a colourlesssolid, (477 mg).

The following were prepared using a method similar to that employed inDescriptions 6 and 7.

1-(3-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine (D8).

1-(4-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine (D9).

1-(6-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine (D10).

Description 11

[1-(6-Methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acidt-butyl ester (D11)

A mixture of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(BINAP, 382 mg), palladium acetate, (92 mg) and caesium carbonate, (3.36g, 10.23 mmol) in dry dioxan (20 ml) was sonicated for 50-60 min to givea pink colour. A solution of 3-t-butoxy-carbonylaminoazetidine acetate(ex. WO 98/57640), (950 mg, 4.09 mmol) and2-chloro-6-methyl-4-trifluoromethylpyridine, (800 mg, 4.09 mmol) in drydioxan (20 ml) was added. The reaction mixture was degassed, flushedwith argon and heated to 100° C. overnight. After work-up with EtOAc andwater, the organic layer was washed with brine, dried (MgSO₄ andactivated charcoal) and concentrated. The crude product was purified bycolumn chromatography to give the title compound as a pale yellow solid,(728 mg, 54%).

Description 12

1-(6-Methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine (D12)

D11, (728 mg, 2.20 mmol) in DCM (5 ml) was treated with TFA (5 ml) atroom temperature for 18 h. The solution was concentrated and partitionedbetween DCM and 2M NaOH. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to give the title compound as a paleyellow crystalline solid (478 mg, 94%).

Description 13

[1-(6-Chloro-5-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acidt-butyl ester (D13)

3-Butoxycarbonylaminoazetidine acetate (synthesis described in WO98/57640) (2 g, 8.61 mmol), 2,6-dichloro-5-trifluoromethylpyridine,(2.05 g, 9.47 mmol) and potassium carbonate, (2.5 g, 18.08 mmol) in dryDMF (20 ml) were heated to 100° C. for 16 h. The 2 isomers wereseparated by column chromatography.[1-(6-chloro-3-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acidt-butyl ester was isolated as a colourless solid, (560 mg, 18%). Thetitle compound,[1-(6-chloro-5-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acidt-butyl ester, was also isolated as a colourless solid (1.92 g, 63%).

Description 14

[1-(6-Methyl-5-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acidt-butyl ester (D14)

A mixture of D13 (1.92 g, 5.55 mmol), methylboronic acid, (490 mg, 8.19mmol) and tetrakis(triphenylphosphine) Pd(0), (315 mg) in dioxan (25 ml)was treated with aqueous sodium carbonate (7 ml). The mixture was heatedat reflux for 16 h, allowed to cool, then diluted with water andextracted with DCM (2×50 ml). The organic phase was washed with brine,dried and concentrated to give a solid. T.I.c anlaysis showed thatsubstantial quantities of starting material remained. The crude materialwas treated again with methylboronic acid, (490 mg, 8.19 mM) andtetrakis(triphenylphosphine) Pd(0), (315 mg) as above. T.I.c. showedcomplete conversion to the product which was purified by columnchromatography to give the title compound as a colourless solid (1.34 g,74%).

Description 15

1-(6-Methyl-5-trifluoromethylpyridin-2-yl)azetidin-3-ylamine (D15)

D14 (1.34 g, 4.04 mmol) was deprotected in a similar manner to thatdescribed in D12 and gave the title compound as a pale yellow oil (849mg, 91%).

Description 16

3-Amino-1-diphenylmethylazetidine (D16)

3-Amino-1-diphenylmethylazetidine was prepared according to theprocedure in J. Heterocyclic. Chem., 1985, 22, 961.

Description 17

3-Amino-1-di-(4-fluorophenyl)methylazetidine (D17)

The title compound was prepared using a method similar to the procedurein J. Heterocyclic. Chem., 1985, 22, 961.

EXAMPLE 1N-(2-Bromophenyl)-N′-[(1-(5-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea(E1)

D7 (100 mg, 0.46 mmol) in dichloromethane (2 ml) at ambient temperaturewas treated with 2-bromophenyl isocyanate (91 mg, 0.46 mmol) indichloromethane (1 ml). The reaction mixture was maintained at ambienttemperature overnight. The white solid was removed by centrifugation andwashed with diethyl ether, and dried in vacuo, to give the titlecompound, (160 mg). MH⁺ 415, 417.

EXAMPLE 2N-(3-Methylisoquinolin-5-yl)-N′-[(1-(5-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea(E2)

D4 (73 mg, 0.46 mmol) in dry dichloromethane (5 ml) was treated withpyridine (45 ul, 0.55 mmol) and phenyl chloroformate (69 ul, 0.55 mmol).After 1 h triethylamine (128 ul, 0.92 mmol) was added, followed by D7(100 mg, 0.46 mmol). The reaction mixture was then stirred overnight atambient temperature. The precipitate was separated by centrifugation,washed with dichloromethane then diethyl ether and then dried to givethe title compound as a yellow solid (129 mg). MH⁺ 402.

EXAMPLES 3-35

Examples presented in Table 1 were prepared in accordance with theprocedures described herein and similar to those of E1 and E2. TABLE 1(IA)

Ex

S r

MH+ 3

1 0

415, 417 4

1 0

415, 417 5

1 0

371, 373 6

1 0

371, 373 7

1 0

355 8

1 0

402 9

1 0

402 10

1 0

402 11

1 0

402 12

1 0

402 13

1 0

402 14

1 0

403 15

1 0

403 16

1 0

403 17

1 0

415, 417 18

1 0

371, 373 19

1 0

371, 373 20

1 0

371, 373 21

1 0

371, 373 22

1 0

405, 407 23

1 0

405, 407 24

1 0

385, 387 25

1 0

405 26

1 0

405 27

1 0

431, 429 28

1 0

416 29

1 0

416 30

1 0

402 31

1 0

419, 421 32

1 0

383, 385 33

1 0

419, 421 34

1 0

383, 385

EXAMPLE 35N-(2-Bromophenyl)-N′-[1-(6-methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-yl]urea(E35)

A mixture of1-(6-methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine, D12 (100mg, 0.432 mM) and 2-bromophenyl isocyanate (86 mg, 0.432 mM) indichloromethane (5 ml) was kept at room temperature overnight. Theresultant solid was removed by centrifugation, washed with diethyl etherand dried in vacuo, to give the title compound as a colourless solid,(119 mg, 64%). MH⁺ 429 and 431; ¹H NMR (250 MHz, d⁶DMSO) δ: 2.39 (3H,s), 3.75-3.88 (2H, dd), 4.30 (2H, t), 4.50-4.66 (1H, m), 6.48 (1H, s),6.78 (1H,s), 6.92 (1H, m), 7.28 (1H, m), 7.57 (1H, dd), 7.76 (1H, d),7.86 (1H, s), and 8.04 (1H, dd).

EXAMPLE 36N-(3-Methylisoquinolin-5-yl)-N′(1-diphenylmethylazetidin-3-yl)-urea(E36)

D4 (73 mg, 0.46 mmol) in dry dichloromethane (5 ml) was treated withpyridine (45 ul, 0.55 mmol) followed by phenyl chloroformate (69 ul,0.55 mmol). After 1 h triethylamine (128 ul, 0.92 mmol) was added,followed by D16 (0.46 mmol). The reaction mixture was then stirredovernight at ambient temperature. The precipitate was separated bycentrifugation, washed with DCM, diethyl ether and then dried to givethe title compound as a yellow solid. MH⁺ 423.

EXAMPLES 37-41

Examples presented in Table 2 were prepared in accordance with theprocedures described herein and similar to those of E36. TABLE 2 (IB)

Ex

(R²)q MH+ 37

H 423 38

H 424 39

H 437 40

4-F 459 41

H 436, 438Pharmacological Data(a) In Vitro Assay

As referenced above, the compounds of the invention are vanilloidreceptor VR1) antagonists and hence have useful pharmaceuticalproperties. Vanilloid receptor (VR1) antagonist activity can beconfirmed and demonstrated for any particular compound by use ofconventional methods, for example those disclosed in standard referencetexts such as D. Le Bars, M. Gozarin and S. W. Cadden, PharmacologicalReviews, 2001, 53(4), 597-652] or such other texts mentioned herein.

The screen used for the compounds of this invention was based upon aFLIPR based calcium assay, similar to that described by Smart et al.(British Journal of Pharmacology, 2000, 129,227-230). Transfectedastrocytoma 1321N1 cells, stably expressing human VR1, were seeded intoFLIPR plates at 25,000 cells/well (96-plate) and cultured overnight.

The cells were subsequently loaded in medium containing 4 μM Fluo-3 AM(Molecular Probes) for 2 h, at room temperature, in the dark. The plateswere then washed 4 times with Tyrode containing 1.5 mM calcium, withoutprobenecid. The cells were pre-incubated with compound or buffer controlat room temperature for 30 min. Capsaicin (Sigma) was then added to thecells. Compounds having antagonist activity against the human VR1 wereidentified by detecting differences in fluorescence when measured aftercapsaicin addition, compared with no compound buffer controls. Thus, forexample, in the buffer control capsaicin addition results in an increasein intracellular calcium resulting in fluorescence. A compound havingantagonist activity blocks the capsaicin binding to the receptor, thereis no signalling and therefore no increase in intracellular calciumlevels and consequently lower fluorescence. pKb values are generatedfrom the IC₅₀ values using the Cheng-Prusoff equation.

All compounds tested by the above methodology (Examples 1-41) had pKb>6,preferred compounds (Examples 1-5,8-13, 16, 20, 22-24, 27-29 and 31-40)having a pKb>7.0.

(b) FCA-Induced Hyperalgesia in the Guinea Pig

100 ul of 1 mg/ml FCA was injected intraplantar into the left paw of 4groups of 8 male Dunkin Hartley guinea-pigs (batch: 6282434, averageweight 340 g). 24 hours later compounds were administered orally at 0(vehicle), 3, 10 30 mg/kg with vehicle as 1% methylcellulose and dosingvolume being 2 ml/kg and dosing straight into the stomach. Themethylcellulose was added gradually to the compound into the pestle andmortar and ground together.

Behavioural readouts of mechanical hyperalgesia were obtained before FCAadministration (naïve reading), after FCA but before drug administration(predose reading) and 1 hour after drug administration. The readout usedwas paw pressure (Randall-Sellito) and the end point was paw withdrawal.The paw pressure equipment also had one silver disc placed on the pointto increase the markings by a factor of 2.

Compounds having a pKb>7.0 in vitro, according to model (a) above, weretested in this model and shown to be active.

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein: P and P′ are independently selected from aryl and heteroaryl;R¹ and R² are independently selected from —H, halo, alkyl, alkoxy,cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN,—NO₂, —OH, —OCF₃, —CF₃, —NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶,—OS(O)₂CF₃, —O(CH₂)_(X)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,—C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(X)OR⁶, —C(O)(CH₂)_(X)NR⁴R⁵,—C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(X)C(O)alkoxy, —(CH₂)_(X)OC(O)R⁶,—(CH₂)_(X)OR⁶, —(CH₂)_(X)NR⁴R⁵, —(CH₂)_(X)C(O)NR⁴R⁵,—(CH₂)_(X)N(R⁴)C(O)R⁶, —(CH₂)_(X)S(O)₂NR⁴R⁵, —(CH₂)_(X)N(R⁴)S(O)₂R⁶,-ZAr, —(CH₂)_(X)S(O)₂R⁶, —(OCH₂)_(X)S(O)₂R⁶, —N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶or —(CH₂)_(X)C(O)alkyl; R⁴ and R⁵ may be the same or different andrepresent H or alkyl or R⁴ and R⁵ together with the atoms to which theyare attached form a C₃₋₆azacycloalkane, C₃₋₆(2-oxo)azacycloalkane ringor C₅₋₈ polymethylene chain optionally interrupted by heteroatoms; Zrepresents O, S or NR⁷; W represents a bond or a group CH or (CH₂)CH; R⁶represents alkyl or aryl; R⁷ represents hydrogen, alkyl or aryl; mrepresents and integer 1 or 2; n represents and integer 0, 1, 2 or 3; pand q independently represent an integer 0, 1, 2, 3 or 4; when W is abond, t represents 1, r represents an integer 0 or 1, and s representsan integer 0 or 1, such that r+s=1; when W is a group CH or (CH₂)CH, trepresents 2, r represents an integer 0, 1, 2 or 3, and s represents aninteger 0, 1 or 2; and x represents an integer 0, 1, 2, 3, 4, 5 or
 6. 2.A compound according to claim 1 wherein P represents phenyl, naphthyl,quinolinyl, cinnolinyl or isoquinolinyl.
 3. A compound according toclaim 1 wherein P′ represents phenyl, pyrimidinyl or pyridyl.
 4. Acompound according to claim 1 wherein R¹ represents halo, —CF₃ or alkyl.5. A compound according to claim 1 wherein p represents 1 or
 2. 6. Acompound according to claim 1 wherein n represents 0 or
 1. 7. A compoundaccording to claim 6 wherein n represents
 0. 8. A compound according toclaim 1 wherein R² represents halo, alkyl, alkoxy, —CN or —CF₃.
 9. Acompound according to claim 1 wherein q represents 0, 1 or
 2. 10. Acompound according to claim 1 wherein q represents 2, P′ represents a6-membered aromatic ring and when W is a bond, R² is 3-trifluoromethyl,4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl,6-methyl-4-trifluoromethyl or 6-methyl-5-trifluoromethyl; and when W isCH or (CH₂)CH, R² is hydrogen or halo.
 11. A compound according to claim1 wherein r+s represents
 1. 12. A compound according to claim 11 whereinr=0 and s=1.
 13. A compound according to claim 1 wherein W represents abond or CH.
 14. A compound according to claim 1 wherein r=0, s=1 and P′represents phenyl or 2-pyridyl.
 15. A compound according to claim 1 asdefined in any one of Examples 1-41 or a pharmaceutically acceptablesalt or solvate thereof.
 16. A compound according to claim 1 selectedfrom:N-(2-Trifluoromethylphenyl)-N′-[(1-(6-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;N-(2-Bromophenyl)-N′-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;N-(2-Chlorophenyl)-N′-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;N-(2,3-Dichlorophenyl)-N′-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;andN-(1-Methylisoquinolin-5-yl)-N′-(1-diphenylmethylazetidin-3-yl)-urea; ora pharmaceutically acceptable salt or solvate of any one thereof.
 17. Acompound according to claim 1 or a pharmaceutically acceptable salt orsolvate thereof for use as an active therapeutic substance.
 18. Apharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier or excipient.
 19. A method for thetreatment or prophylaxis of disorders in which antagonism of theVanilloid (VR1) receptor is beneficial in mammal, which method comprisesadministering to a mammal in need thereof a therapeutically acceptableamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt or solvate thereof.
 20. (canceled)
 21. The methodaccording to claim 19 wherein the disorder is selected from pain,chronic pain, neuropathic pain, postoperative pain, postrheumatoidarthritic pain, osteoarthritic pain, back pain, visceral pain, cancerpain, algesia, neuralgia, dental pain, headache, migraine, neuropathies,carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy,post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury,ischaemia, neurodegeneration, stroke, post stroke pain, multiplesclerosis, respiratory diseases, asthma, cough, COPD, bronchoconstriction, inflammatory disorders, oesophagitis, heart burn,Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder(GERD), stomach and duodenal ulcers, functional dyspepsia, irritablebowel syndrome, inflammatory bowel disease, colitis, Crohn's disease,pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic,urinary incontinence, cystitis, burns, itch, psoriasis, pruritis andemesis.
 22. A process for the production of a compound according toclaim 1 which process comprises coupling a compound of formula (II):

in which R¹, P and p are as defined in claim 1 with a compound offormula (III):

in which P′, R², W, n, q, r, s and t are as defined in claim 1 and A andB contain appropriate functional groups which are capable of reactingtogether to form the urea moiety; and thereafter, as necessary, carryingout one or more of the following reactions: (i) converting one compoundof formula (I) into another compound of formula (I); (ii) removing anyprotecting group; (iii) preparing a salt or a solvate of the compound soformed.
 23. A compound of formula (IIIA):

in which P′, R², W, n, q, r, s and t are as defined in formula (I) ofclaim 1 and B is NH₂ or N═C═O.
 24. A compound according to claim 23selected from: 1-(5-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;1-(3-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;1-(4-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;1-(6-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;1-(6-Methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;1-(6-Methyl-5-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;3-Amino-1-diphenylmethylazetidine; and3-Amino-1-di-(4-fluorophenyl)methylazetidine.